For chemotherapy of human tumors, alkylating agents, antimetabolites, antitumor antibiotics, platinum compounds and the like have been used. When single uses of these activating agents do not exhibit marked therapeutic effects, therapies in which multiple drugs are used in combination have been considered (Frei, E. III, Cancer Res. (1992) 32, 2593-2607). As anticancer agents that belong to the alkylating agents, there are mentioned nitrogen mustard anticancer agents, which is a general term used for the anticancer agents that have a partial structure called nitrogen mustard. Of the nitrogen mustard anticancer agents melphalan has been put into practical use.
IL-6 is a multifunctional cytokeine called B-cell stimulatory factor 2 or interferon β2. IL-6 was discovered as a differentiation factor responsible for activation of B-lymphocytes (Hirano, T. et al., Nature (1986) 324, 73-76). Thereafter, it was found to be a multifunctional cytokeine that influences the function of various cells (Akira, S. et al., Adv. in Immunology (1993) 54, 1-78). IL-6 imparts its biological activity through two proteins on the cell membrane.
One of them is a ligand-biding protein with a molecular weight of about 80 kD, IL-6 receptor, to which IL-6 binds. IL-6 receptor occurs not only in a membrane-bound form that penetrates and is expressed on the cell membrane but also as a soluble IL-6 receptor consisting mainly of the extracellular region. The other is non-ligand-binding gp130 with a molecular weight of about 130 kD that takes part in signal transmission. IL-6 and IL-6 receptor form a IL-6/IL-6 receptor complex, to which another membrane protein gp130 is bound, and thereby the biological activity of IL-6 is transmitted to the cell (Taga et al., J. Exp. Med. (1987) 166, 967).
Antibodies to IL-6 receptor (anti-IL-6 receptor antibodies) have been known (Novick D. et al., Hybridoma (1991) 10, 137-146 Huang, Y. W. et al., Hybridoma (1993) 12, 621-630 International Patent Application WO95-09873, French Patent Application FR 2694767, U.S. Pat. No. 5,216,128), one of which is PM-1 derived from mice (Hirata et al., J. Immunology (1989) 143, 2900-2906). Furthermore, a reshaped antibody obtained by replacing the complementarity determining regions (CDRs) of the mouse antibody with the CDRs of a human antibody has also been known.
However, the combined use of a nitrogen mustard anticancer agent and IL-6 receptor as a therapeutic agent for treatment of myeloma has not been known.